Huntington's disease is a progressive neurodegenerative disorder caused by polyglutamine-encoding muta- tional expansion of the huntingtin gene. While symptomatic treatments are available, Huntington's disease is presently not curable;there are no therapeutic agents that address the underlying neuronal cell death asso- ciated with the disorder. Accordingly, there is a critical need to identify new compounds for preclinical devel- opment against Huntington's disease. The long-term goal of this research is to identify therapeutic strategies that help alleviate the devastating impact of Huntington's disease on patients and their families. The central hypothesis of this study is that targeted, assay-guided isolation of natural products, coupled with semi-synthetic optimization of their bioactivity, will yield compounds with curative potential against Huntington's disease. Therefore, the objective of this translational R21 study is responsive to the NINDS program announcement, "Exploratory/Development Projects in Translational Research," as we will identify candidate therapeutics pre- venting cell death by inhibiting and/or disrupting toxicity of the aggregation-prone form of mutant huntingtin. Our preliminary studies, focused on the screening of a chemically and biologically diverse extract library, yielded several lead natural products that are capable of protecting cells against mutant huntingtin toxicity. The rationale for this research is that as a consequence of obtaining 1) additional naturally-occurring congen- ers of the bioactive principles and 2) preparing derivatives of the active leads via semi-synthesis, we will be able to refine our focus to one or two of the most promising candidate compounds that will serve as therapeutic leads for subsequent U01 preclinical studies. Based on the success of our preliminary investigation, the fol- lowing two specific aims will be addressed. In Specific Aim 1, plants and fungi that are biosystematically- related to the organisms which provided the original natural product leads will be subjected to assay-guided isolation to identify new bioactive congeners of the lead compounds. Under Specific Aim 2, the bioactive lead natural products and their analogs will be further probed by subjecting them to a judicious series of derivatiza- tion procedures that expand on their favorable biological activities. All compounds and derivatives emerging from this work will be critically evaluated in a mammalian-cell-based mutant-huntingtin expression system and the best small-molecule candidates will advance for screening in a mouse model of Huntington's disease. This method will generate a focused series of lead compounds exhibiting enhanced potency and improved biophys- ical features (e.g. good predicted blood-brain-barrier penetration) that are well suited for focused preclinical studies. Our approach is innovative because natural products, an exceptional source of bioactive drug-like lead compounds, have not been systematically evaluated for the discovery of neuroprotective agents against Hun- tington's disease. Furthermore, these samples offer an unprecedented opportunity to identify small-molecule leads that are structurally distinct with pharmacologically novel modes-of-action. This research is significant because candidate therapeutic agents evolving from this research will be particularly well suited for detailed preclinical evaluation and development under the auspices of the U01 mechanism. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because 1) there is currently no cure for treating Hunting- ton's disease and 2) candidate compounds emerging from these studies could find applications in the treat- ment of this and other related polyglutamine expansion disorders. Therefore, this research will ultimately have a positive impact on the health and well-being of patients and families afflicted by Huntington's disease and other neurodegenerative illnesses.